The Crystal Structures of Two Isomers of 5-(Phenylisothiazolyl)-1, 3, 4
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research communications The crystal structures of two isomers of 5-(phenyl- isothiazolyl)-1,3,4-oxathiazol-2-one ISSN 2056-9890 Shuguang Zhu,a Melbourne J. Schriver,b* Arthur D. Hendsbeec and Jason D. Masudac aTeva Pharmaceuticals, 3333 N Torrey Pines Ct, Suite 400, La Jolla, CA 92130, bDepartment of Chemistry, Crandall c Received 14 September 2017 University, PO Box 6004, Moncton, New Brunswick, E1C 9L7, Canada, and The Atlantic Centre for Green Chemistry Accepted 16 October 2017 and the Department of Chemistry, Saint Mary’s University, Halifax, Nova Scotia, B3H 3C3, Canada. *Correspondence e-mail: [email protected] Edited by W. T. A. Harrison, University of The syntheses and crystal structures of two isomers of phenyl isothiazolyl Aberdeen, Scotland oxathiazolone, C11H6N2O2S2, are described [systematic names: 5-(3-phenyliso- thiazol-5-yl)-1,3,4-oxathiazol-2-one, (I), and 5-(3-phenylisothiazol-4-yl)-1,3,4- Keywords: crystal structure; isothiazoyl; oxa- oxathiazol-2-one, (II)]. There are two almost planar (r.m.s. deviations = 0.032 thiazolone; conjugation; nitrile sulfide; - and 0.063 A˚ ) molecules of isomer (I) in the asymmetric unit, which form stacking. centrosymmetric tetramers linked by strong SÁÁÁN [3.072 (2) A˚ ]andSÁÁÁO ˚ CCDC references: 1580338; 1580337 contacts [3.089 (1) A]. The tetramers are -stacked parallel to the a-axis direction. The single molecule in the asymmetric unit of isomer (II) is twisted Supporting information: this article has into a non-planar conformation by steric repulsion [dihedral angles between the supporting information at journals.iucr.org/e central isothiazolyl ring and the pendant oxathiazolone and phenyl rings are 13.27 (6) and 61.18 (7), respectively], which disrupts the -conjugation between the heteroaromatic isothiazoloyl ring and the non-aromatic oxathiazolone heterocycle. In the crystal of isomer (II), the strong SÁÁÁO [3.020 (1) A˚ ]and SÁÁÁC contacts [3.299 (2) A˚ ] and the non-planar structure of the molecule lead to a form of -stacking not observed in isomer (I) or other oxathiazolone derivatives. 1. Chemical context Compounds containing the isothiazolyl moiety are well known in organic and pharmacological research, with extensive reviews on the synthesis and chemistry of the ring (Abdel- Sattar & Elgazwy, 2003) and the medicinal and industrial uses of compounds containing the isothiazolyl heterocycle (Kaberdin & Potkin 2002). The solid-state structural features of isothiazole derivatives have been reviewed (Abdel-Sattar & Elgazwy, 2003). In general, the isothiazolyl ring is recognised as a heteroaromatic ring with extensive -delocalization (incorporating the empty sulfur 3d-orbitals) within the ring leading to almost planar heterocycles. Derivatives of the oxathiazolone heterocycle have been known since their first preparation fifty years ago (Muhlbauer & Weiss, 1967). The facile synthesis of the heterocycle from commercially available amides reacting with chlorocarbonyl sulfenyl chloride under a range of conditions has resulted in the publication of significant libraries of substituted oxathia- zolone compounds (Senning & Rasmussen, 1973; Howe et al., 1978; Lin et al., 2009; Fordyce et al., 2010; Russo et al., 2015) leading to hundreds of known oxathiazolone derivatives. The predominant chemistry of the heterocycle has been the thermal cycloreversion to the short lived nitrile sulfide [R— C N(+)—S(À)] , a propargyl allenyl 1,3-dipole, which can be 1726 https://doi.org/10.1107/S2056989017015067 Acta Cryst. (2017). E73, 1726–1731 research communications trapped by electron-deficient bonds in reasonable yield to give families of new heterocycles (Paton, 1989), including isothiazole derivatives. As a result of the electronic properties of the short-lived nitrile sulfide intermediates, optimal condi- tions for cyclization require trapping reactions with electron- deficient dipolariphiles. Industrially, various derivatives of the oxathiazolone heterocycle have been reported as potential fungicides (Klaus et al., 1965), pesticides (Ho¨lzl, 2004) and as polymer additives (Crosby 1978). More recently, the medicinal properties of the oxathiazolone heterocycle have been explored as selective inhibitors for tuberculosis (Lin et al., 2009), inflammatory diseases (Fan et al., 2014) and as proteasome inhibitors (Russo et al., 2015). In previous structural studies on oxathiazolone compounds, the non-aromatic heterocyclic rings were found to be planar with largely localized C N and C O double bonds. The extent of -delocalization within the oxathiazolone ring and to the substituent group and the effect on the structure and chemical properties have been discussed spectroscopically (Markgraf et al., 2007) and structurally (Krayushkin et al., 2010a,b). Our interest in this system was prompted by the possibility that catenated systems of isothiazolone hetero- Figure 1 The molecular structure of (I), showing 50% probability displacement cycles may have useful electronic properties as the number of ellipsoids. systems is increased. analysis, we will restrict our discussion to the first molecule in the asymmetric unit. The asymmetric unit of (II) is shown in Fig. 2. The bond distances and angles within the terminal phenyl rings in compounds (I) and (II) are not significantly different from the those reported for related compounds (Schriver & Zaworotko, 1995; Krayushkin et al., 2010a,b). The sum of the endocyclic bond angles in the isothiazole moieties for both (I) and (II) (540.0) is consistent with planar (ideal sum = 540) -delocalized five-membered rings, as expected. The bond lengths of the endocyclic bonds in the isothiazolyl moieties in (I) and (II) are not significantly ( >3) different from the 2. Structural commentary There are two independent molecules in the asymmetric unit of (I) (Fig. 1). In general, the two molecules are not signifi- cantly different with the exception of the C—S bonds in the oxathiazolone rings. In one of the molecules, the C1—S1 distance [1.762 (2) A˚ ] is longer than the same bond in the second molecule, C12—S3 [1.746 (2) A˚ ]. The difference may arise from the nature of the intermolecular contacts to the sulfur atoms, with a strong pair of co-planar SÁÁÁN contacts [3.086 (2) A˚ ] in the first molecule but only one SÁÁÁN contact [3.072 (2) A˚ ] in the second molecule (which is also twisted out of the plane of the molecule). These differences are due to the Figure 2 position of the independent molecules in the tetramer that will The molecular structure of (II), showing 50% probability displacement be described below. For the purposes of further structural ellipsoids. Acta Cryst. (2017). E73, 1726–1731 Zhu et al. C11H6N2O2S2 and C11H6N2O2S2 1727 research communications statistical averages from previous structural studies (Bridson the pendant oxathiazolone and phenyl rings being 3.06 (11) et al., 1994, 1995). While the C N bonds in the isothiazolyl and 1.10 (12), respectively, for the S1 molecule and 2.62 (9) rings of (I) [1.327 (3) A˚ ] and (II) [1.321 (2) A˚ ] and the C C and 6.84 (10), respectively, for the S3 molecule. Overall r.m.s. bonds in (I) [1.361 (3) A˚ ] and (II) [1.374 (2) A˚ ] are mostly deviations for the S1 and S3 molecules are 0.032 and 0.063 A˚ , longer than the statistical averages for C N [1.308 Æ 0.016 A˚ ] respectively. In contrast to the near planarity of both asym- and C C bonds [1.369 Æ 0.002 A˚ ], the differences are not metric molecules of (I), the single molecule of (II) features sufficient to warrant an assessment of their cause or their significant twists between the central isothiazolyl ring and the effect on the structure. pendant oxathiazolone and phenyl rings [dihedral angles of The bond distances and angles within the oxathiazolone 13.27 (6) and 61.18 (7), respectively], which may be ascribed rings in compounds (I) and (II) are not significantly different to steric crowding. It has been argued, based on spectroscopic ( 3) from the statistical averages for published crystal and structural evidence, that -delocalization extends structures (Schriver & Zaworotko, 1995; Bridson et al. 1994, between the rings of oxathiazolone heterocycles attached to 1995; Vorontsova et al., 1996; McMillan et al., 2006; aromatic rings, resulting in observable differences (Schriver & Krayushkin et al., 2010a,b; Nason et al., 2017). The sum of the Zaworotko, 1995; Krayushkin et al., 2010a,b; Markgraf et al., endocyclic bond angles in the oxathiazolone rings for both (I) 2007). In this work it can be seen that nearly identical mol- and (II) (540.0) is consistent with planar rings (ideal sum = ecules result, even when torsion angles are present that would 540). The S—N bonds in the oxathiazolone rings of (I) effectively disrupt any conjugation between the rings, ˚ ˚ [1.685 (2) A] and (II) [1.682 (1) A], the Csub—O bonds in (I) suggesting that the presence or absence of inter-ring delo- [1.364 (2) A˚ ] and (II) [1.375 (1) A˚ ] and the inter-ring Csp2— calization does not have a significant effect on the structure of Csp2 bonds in (I) [1.449 (3) A˚ ] and (II) [1.451 (2) A˚ ] are all the molecules. consistently shorter than the statistical averages for S—N ˚ ˚ [1.696 Æ 0.022 A], Csub—O [1.392 Æ 0.030 A] and C C bonds [1.461 Æ 0.025 A˚ ]. These differences, however, are not suffi- 3. Supramolecular features cient to warrant an assessment of their cause or their effect on In all previous reports on the solid-state structures of the structure. compounds containing the oxathiazolone heterocycle, the The three rings in the molecules of (I) are nearly co-planar, intermolecular interactions have been ignored or described as with the dihedral angles between central isothiazolyl ring and insignificant, with the exception of the recent observation of Figure 3 A packing diagram of (I) showing – stacking parallel to the a-axis direction (top). Co-planar paired head-to-head molecules [green lines, SÁÁÁN distance of 3.086 (2) A˚ ] and paired molecules separated by out-of-plane contacts [blue lines, SÁÁÁN distance of 3.072 (2) A˚ ], violet lines SÁÁÁO distance of 3.089 (1) A˚ ].